The erbB family of receptor tyrosine kinases, which include EGFR, erbB2, erbB3 and erbB4, are frequently involved in driving the proliferation and survival of tumour cells and as such the erbB family of receptors is implicated in a number of epithelial cancers (reviewed in Olayioye et al., EMBO J., 2000, 19, 3159), including for example breast cancer (Sainsbury et al., Brit. J. Cancer, 1988, 58, 458; Guerin et al., Oncogene Res., 1988, 3, 21; Slamon et al., Science, 1989, 244, 707; Klijn et al., Breast Cancer Res. Treat., 1994, 29, 73 and reviewed in Salomon et al., Crit. Rev. Oncol. Hematol., 1995, 19, 183), non-small cell lung cancers (NSCLCs) including adenocarcinomas (Cerny et al., Brit. J. Cancer, 1986, 54, 265; Reubi et al., Int. J. Cancer, 1990, 45, 269; Rusch et al., Cancer Research, 1993, 53, 2379; Brabender et al, Clin. Cancer Res., 2001, 7, 1850) as well as other cancers of the lung (Hendler et al., Cancer Cells, 1989, 7, 347; Ohsaki et al., Oncol. Rep., 2000, 7, 603), bladder cancer (Neal et al., Lancet, 1985, 366; Chow et al., Clin. Cancer Res., 2001, 7, 1957, Zhau et al., Mol Carcinog., 3, 254), oesophageal cancer (Mukaida et al., Cancer, 1991, 68, 142), gastrointestinal cancer such as colon, rectal or stomach cancer (Bolen et al., Oncogene Res., 1987, 1, 149; Kapitanovic et al., Gastroenterology, 2000, 112, 1103; Ross et al., Cancer Invest., 2001, 19, 554), cancer of the prostate (Visakorpi et al., Histochem. J., 1992, 24, 481; Kumar et al., 2000, 32, 73; Scher et al., J. Natl. Cancer Inst., 2000, 92, 1866), leukaemia (Konaka et al., Cell, 1984, 37, 1035, Martin-Subero et al., Cancer Genet Cytogenet., 2001, 127, 174), ovarian (Hellstrom et al., Cancer Res., 2001, 61, 2420), head and neck (Shiga et al., Head Neck, 2000, 22, 599) or pancreatic cancer (Ovotny et al., Neoplasma, 2001, 48, 188).
Accordingly it has been recognised that an inhibitor of erbB receptor tyrosine kinases should be of value as a selective inhibitor of the growth of certain carcinomas. A number of erbB tyrosine kinase inhibitors have demonstrated clinical benefit and a number of erbB tyrosine kinase inhibitors have been approved for use in the treatment of cancer. For example, the EGFR tyrosine kinase inhibitors gefitinib and erlotinib for the treatment of advanced non-small cell lung cancer and lapatinib, which has erbB2 tyrosine kinase inhibitory activity, for use in metastatic breast cancer. Several other EGFR and erbB2 tyrosine kinase inhibitors are currently in development.
Compound (I) is disclosed in International Patent Application Publication number WO2005/028469 as Example 1 therein and is of the structure:

Compound (I) is an erbB receptor tyrosine kinase inhibitor, in particular Compound (I) is a potent inhibitor of EGFR and erbB2 receptor tyrosine kinases.
There is a growing body of pre- and clinical evidence suggesting that, in addition to signalling via EGFR and erbB2 homodimers, cell signalling mediated by EGFR, erbB2 & erbB3 heterodimers may be an important oncogenic signalling pathway (Sergina et al., Nature, 2007, 445, 437; Ritter et al., Clin Cancer Res. 2007, 13, 4909; Johnston et al., JCO, 2008, 26, 1066). Since erbB3 does not have an intrinsic tyrosine kinase activity, activation of the erbB3 receptor is achieved only through the formation of heterodimeric receptor complexes with other kinase-active receptors including particularly EGFR and erbB2. EGFR and erbB2 heterodimers formed with erbB3 are thought to drive tumour growth in tumours where these receptors are expressed.
We have found in pre-clinical experiments that Compound (I) also inhibits erbB3 mediated signalling through the inhibition of phosphorylation of erbB3 following ligand stimulated EGFR/erbB3 and/or erbB2/erbB3 heterodimerisation. Accordingly, Compound (I) exhibits a unique erbB tyrosine kinase inhibitory effect compared to other erbB tyrosine kinase inhibitors such as gefitinib or erlotinib that act primarily as EGFR tyrosine kinase inhibitors. We have carried out pre-clinical studies which suggest that Compound (I) exhibits improved anti-tumour effects compared to EGFR tyrosine kinase inhibitors such as gefitinib and erlotinib. Without wishing to be bound by theory, it is thought that the improved properties may result from the inhibition of the erbB3 mediated signalling by Compound (I).
WO2005/028469 indicates that the compounds disclosed therein may be prepared in the form of a pharmaceutically acceptable salt, for example, an acid-addition salt of a compound of the Formula I, with an inorganic or organic acid such as hydrochloric, hydrobromic, sulfuric, trifluoroacetic, citric or maleic acid. Nowhere in WO2005/028469 is there a suggestion of a salt with fumaric acid. Compound (I) is disclosed in Example 1 of WO2005/028469 and is isolated as the free base. There is no disclosure in WO2005/028469 of any specific salt of Compound (I).
We have found that Compound (I) is crystalline with some amorphous character as shown in the XRPD of FIG. 1. Differential scanning calorimetry (FIG. 2A) on Compound (I) shows a broad endotherm with an onset of 76.2° C., which is likely to be due to solvent loss, most likely water, followed by a melting endotherm with an onset of 126.2° C. Thermogravimetric analysis on Compound (I) (FIG. 2B) shows a weight loss of 1.2% between 25° C. and 95° C.
Dynamic Vapour Sorption (FIG. 3) shows moisture uptake of approximately 1.9% w/w at 80% relative humidity, accordingly Compound (I) is moderately hygroscopic.
We have found that Compound (I) has a relatively low intrinsic dissolution rate, particularly at pH below 6.0 and has a high cellular permeability. The low solubility and high permeability suggest a BCS classification of Class II for Compound (I). Therefore, the dissolution characteristics of the compound may be critical in controlling drug absorption and inter patient variability, especially at higher doses. These findings together with the facts that Compound (I) is partially amorphous and is hygroscopic has resulted in the need to find alternative forms of Compound (I) with improved properties.
We have surprisingly found that the difumarate salt of Compound (I) has favourable properties compared to Compound (I). Compound (I) difumarate has a favourable dissolution profile exhibiting, high aqueous solubility and a good intrinsic dissolution rate. Furthermore, the Compound (I) difumarate exhibits favourable solid-state properties, for example high crystallinity, low hygroscopicity and/or favourable thermal properties, such as a high melting point.